PROJECT SUMMARY Males are more likely to engage in risky behaviors that are characterized by lack of behavioral inhibition than are females. In addition, males are more likely than females to be diagnosed with neuropsychiatric disorders that are characterized by decreased behavioral inhibition or impulse control. The basis for this sex difference is likely complex, but is also likely to include a biological component. The long-term goal of the current research is to elucidate brain mechanisms that mediate increased biological vulnerability exhibited by males as compared to females to disorders of impulse control. The prefrontal cortex is thought to influence impulsivity by modulating operations of lower brain areas, including the striatum, that are involved in mediating motor output and reward-based behaviors. Cortical input to the dorsal striatum provides innervation to two primary projection pathways that have opposing effects on behavioral output. Activation of the so-called direct pathway of the striatum facilitates motor output, whereas activation of the indirect pathway inhibits motor output. Coordinated activity of these two pathways is thought to provide for release of desired behaviors while inhibiting undesired ones. The central hypothesis to be tested by the currently proposed experiments is that the relative contributions of the striatal direct and indirect pathways for control of motor output differ between the sexes, with females having increased input from the prefrontal cortex to the dorsal striatum as compared to males allowing for greater cortical control and activation of the striatal indirect pathway over the striatal direct pathway resulting in greater inhibitory control over behavior in females than in males. This hypothesis will be tested by two specific aims. In the first aim, we will determine if males and females have differential levels of prefrontal cortex innervation of direct- and indirect-pathway striatal projection neurons. To achieve this aim, we will use newly available Cre-expressing transgenic rat lines combined with a monosynaptic rabies virus system allowing us to specifically target direct or indirect projection neurons in the striatum and label their monosynaptic inputs. For our second aim, we will determine if the relative contributions of the striatal indirect and direct pathways in the modulation of impulse control varies between males and females. To achieve this second aim, we will use the same transgenic rat lines in combination with designer receptors exclusively activated by designer drugs (DREADD) technology to selectively ?turn off? neurons of the indirect pathway or ?turn on? neurons of the direct pathway and assess levels of impulse control during performance on the 5- choice serial reaction time task, a well-established assay of attentional processes and impulse control in rodents. The completion of the proposed aims will provide the first assessment of potential sex differences in cortical control over direct- and indirect-pathway striatal projection neurons. Results have implications for understanding the biological basis of male vulnerability to disorders of impulse control.